Open AccessMachine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation
Author(s) -
Tathiane M. Malta,
Artem Sokolov,
Andrew J. Gentles,
Tomasz Burzykowski,
Laila Poisson,
John N. Weinstein,
Bożena Kamińska,
Joerg Huelsken,
Larsson Omberg,
Olivier Gevaert,
Antonio Colaprico,
Patrycja Czerwińska,
Sylwia Mazurek,
Lopa Mishra,
Holger Heyn,
A. Krasnitz,
Andrew K. Godwin,
Alexander J. Lazar,
Joshua M. Stuart,
Katherine A. Hoadley,
Peter W. Laird,
Houtan Noushmehr,
Maciej Wiznerowicz,
Rory Johnson,
John A. Demchok,
Ina Felau,
Melpomeni Kasapi,
Martin L. Ferguson,
Carolyn M. Hutter,
Heidi J. Sofia,
Roy Tarnuzzer,
Zhining Wang,
Liming Yang,
Jean C. Zenklusen,
Jiashan Zhang,
Sudha Chudamani,
Jia Liu,
Laxmi Lolla,
Rashi Naresh,
Todd Pihl,
Qiang Sun,
Yunhu Wan,
Ye Wu,
Juok Cho,
Timothy Defreitas,
Scott Frazer,
Nils Gehlenborg,
Gad Getz,
David I. Heiman,
Jaegil Kim,
Michael S. Lawrence,
Pei Lin,
Thomas J. Giordano,
Michael S. Noble,
Gordon Saksena,
Doug Voet,
Hailei Zhang,
Brady Bernard,
Nyasha Chambwe,
Varsha Dhankani,
Theo Knijnenburg,
Roger Kramer,
Kalle Lein,
Yuexin Liu,
Michael B. Miller,
Sheila M. Reynolds,
Ilya Shmulevich,
Vésteinn Thórsson,
Wei Zhang,
Rehan Akbani,
Bradley M. Broom,
Apurva M. Hegde,
Zhenlin Ju,
Rupa S. Kanchi,
Anil Korkut,
Jun Li,
Han Liang,
Shiyun Ling,
Wenbin Liu,
Yiling Lu,
Gordon B. Mills,
Kwok-Shing Ng,
Arvind Rao,
Michael T. Ryan,
Jing Wang,
Jiexin Zhang,
Adam Abeshouse,
Joshua Armenia,
Debyani Chakravarty,
Walid K. Chatila,
Ino de Bruijn,
Galen F. Gao,
Benjamin Groß,
Zachary Heins,
Ritika Kundra,
Konnor La,
Marc Ladanyi,
Augustin Luna,
Moriah G. Nissan,
Angelica Ochoa,
Sarah Phillips,
Ed Reznik,
Francisco Sánchez-Vega,
Chris Sander,
Nikolaus Schultz,
Robert E. Sheridan,
S. Onur Sumer,
Yichao Sun,
Barry S. Taylor,
Jioajiao Wang,
Hongxin Zhang,
Pavana Anur,
Myron Peto,
Paul T. Spellman,
Christopher C. Benz,
Christopher K. Wong,
Christina Yau,
D. Neil Hayes,
Peter J. Park,
Matthew D. Wilkerson,
Adrian Ally,
Miruna Balasundaram,
Reanne Bowlby,
Denise Brooks,
Rebecca Carlsen,
Eric Chuah,
Noreen Dhalla,
Robert A. Holt,
Steven J.M. Jones,
L. Sylvia,
Darlene Lee,
Yussanne Ma,
Marco A. Marra,
Michael Mayo,
Richard A. Moore,
Andrew J. Mungall,
Karen Mungall,
Lewis R. Roberts,
Sara Sadeghi,
Jacqueline E. Schein,
Payal Sipahimalani,
Angela Tam,
Nina Thiessen,
Kane Tse,
Tina Wong,
Ashton C. Berger,
Rameen Beroukhim,
Andrew D. Cherniack,
Carrie Cibulskis,
Stacey Gabriel,
Gavin Ha,
Matthew Meyerson,
Steven E. Schumacher,
Juliann Shih,
Melanie H. Kucherlapati,
Raju Kucherlapati,
Stephen Baylin,
Leslie Cope,
Ludmila Danilova,
Moiz Bootwalla,
Phillip H. Lai,
Dennis T. Maglinte,
David Van Den Berg,
Daniel J. Weisenberger,
J. Todd Auman,
Saianand Balu,
Tom Bodenheimer,
Huihui Fan,
Alan P. Hoyle,
Corbin D. Jones,
Shaowu Meng,
Piotr A. Mieczkowski,
Lisle E. Mose,
Amy H. Perou,
Charles M. Perou,
Jeffrey Roach,
Yan Shi,
Janae V. Simons,
Tara Skelly,
Matthew G. Soloway,
Donghui Tan,
Umadevi Veluvolu,
Toshinori Hinoue,
Hui Shen,
Wanding Zhou,
Michelle Bellair,
Kyle Chang,
Kyle R. Covington,
Chad J. Creighton,
Huyen Dinh,
HarshaVardhan Doddapaneni,
Lawrence A. Donehower,
Jennifer Drummond,
Richard A. Gibbs,
Robert Glenn,
Walker Hale,
Yi Han,
Hai Hu,
Viktoriya Korchina,
Charles Lee,
Lora Lewis,
Wei Li,
Xiuping Liu,
Margaret Morgan,
Donna Morton,
Donna M. Muzny,
Jireh Santibanez,
Margi Sheth,
Eve Shinbrot,
Linghua Wang,
Min Wang,
David A. Wheeler,
Xi Liu,
Fengmei Zhao,
Julian M. Hess,
Elizabeth L. Appelbaum,
Matthew H. Bailey,
Matthew G. Cordes,
Li Ding,
Catrina C. Fronick,
Lucinda A. Fulton,
Robert S. Fulton,
Cyriac Kandoth,
Elaine R. Mardis,
Michael D. McLellan,
Christopher A. Miller,
Heather K. Schmidt,
Richard K. Wilson,
Daniel Crain,
Erin Curley,
Johanna Gardner,
Kevin Lau,
David Mallery,
Scott Morris,
Joseph Paulauskis,
Robert Penny,
Candace Shelton,
Troy Shelton,
Mark E. Sherman,
Eric Thompson,
Peggy Yena,
Jay Bowen,
Julie M. Gastier-Foster,
Mark Gerken,
Kristen Leraas,
Tara M. Lichtenberg,
Nilsa C. Ramirez,
Lisa Wise,
Erik Zmuda,
Niall M. Corcoran,
Tony Costello,
Christopher M. Hovens,
André Lopes Carvalho,
Ana Carolina de Carvalho,
José Humberto Tavares Guerreiro Fregnani,
Adhemar LongattoFilho,
Rui Manuel Reis,
Cristovam ScapulatempoNeto,
Henrique C.S. Silveira,
Daniel Onofre Vidal,
Andrew Burnette,
Jennifer Eschbacher,
Beth Hermes,
Ardene Noss,
Rosy Singh,
Matthew L. Anderson,
Patricia D. Castro,
Michael Ittmann,
David Huntsman,
Bernard Kohl,
Xuan Le,
Richard Thorp,
Chris Andry,
Elizabeth R. Duffy,
Vladimir Lyadov,
Oxana Paklina,
Galiya Setdikova,
Shabunin Av,
Mikhail Tavobilov,
Christopher McPherson,
Ronald E. Warnick,
Ross S. Berkowitz,
Daniel Cramer,
Colleen M. Feltmate,
Neil S. Horowitz,
Adam S. Kibel,
Michael G. Muto,
Chandrajit P. Raut,
Andrei Malykh,
Jill S. BarnholtzSloan,
Wendi Barrett,
Karen Devine,
Jordonna Fulop,
Quinn T. Ostrom,
Kristen Shimmel,
Yingli Wolinsky,
Andrew E. Sloan,
Agostino Maria De Rose,
Felice Giuliante,
Marc T. Goodman,
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Jodi Harr,
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Kelinda Tucker,
Leigh Anne Zach,
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Dirk Schadendorf,
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Pierre Tennstedt,
Oluwole Olabode,
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Ashley Fehrenbach,
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Ruth Steele,
Antonio Jimeno,
Francis A. Carey,
Ian Forgie,
Massimo Mannelli,
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Brenda Hernandez,
Benito Campos,
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Tina Knutson,
Deqin Ma,
Mohammed Milhem,
Rita Sigmund,
Rashna Madan,
Howard G. Rosenthal,
Clement Adebamowo,
Sally N. Adebamowo,
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David G. Beer,
AnneMarie MesMasson,
Fred Saad,
Thèrése Bocklage,
Lisa M. Landrum,
Robert S. Mannel,
Kathleen N. Moore,
Katherine Moxley,
Russel Postier,
Joan L. Walker,
Rosemary E. Zuna,
Michaël Feldman,
Federico Valdivieso,
Rajiv Dhir,
James D. Luketich,
Edna M. Mora Pinero,
Mario Quintero-Aguilo,
Carlos Gilberto Carlotti,
José Sebastião dos Santos,
Rafael Kemp,
Ajith Sankarankuty,
Daniela Pretti da Cunha Tirapelli,
James W.F. Catto,
Kathy Agnew,
Elizabeth M. Swisher,
Jenette Creaney,
Bruce Robinson,
Carl Simon Shelley,
Eryn M. Godwin,
Sara Kendall,
Cassaundra Shipman,
Carol R. Bradford,
Thomas E. Carey,
Robert I. Haddad,
Jeffey Moyer,
Lisa A. Peterson,
Mark E. Prince,
Laura S. Rozek,
Gregory T. Wolf,
Rayleen Bowman,
Kwun M. Fong,
Ian A. Yang,
Robert J. Korst,
W. Kimryn Rathmell,
J. Leigh Fantacone-Campbell,
Jeffrey A. Hooke,
Albert J. Kovatich,
Craig D. Shriver,
John F. DiPersio,
Bettina F. Drake,
Ramaswamy Govindan,
Sharon E. Heath,
Timothy J. Ley,
Brian A. Van Tine,
Peter Westervelt,
Mark A. Rubin,
Jung Il Lee,
Natália D. Aredes,
Armaz Mariamidze
Publication year - 2018
Publication title -
cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 26.304
H-Index - 776
eISSN - 1097-4172
pISSN - 0092-8674
DOI - 10.1016/j.cell.2018.03.034
Subject(s) - biology , phenotype , tumor microenvironment , induced pluripotent stem cell , epigenetics , cancer stem cell , transcriptome , progenitor cell , cancer research , stem cell , cancer , computational biology , genetics , embryonic stem cell , gene , gene expression
Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.
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